Virtual tissues

These may be produced by grouping together multiple cell models to form virtual tissue segments, or even the whole organ. The validity of such multi-cellular constructs crucially depends on whether or not they take into account the heart s fine architecture, as cardiac structure and function are tightly interrelated. 

Knudsen TB, Daston GP (2010) Virtual tissues and developmental systems biology. In McQueen CA (ed) Comprehensive toxicology, vol 12. Academic, Oxford, pp 347-358... 

Due to its central role in toxicant metabolism, the liver is one of the first organs being constructed in the Virtual Tissue Research Project. Physiologically based pharmacokinetic modeling, cellular systems, and molecular networks are integrated to mimic the multitude of activities performed by the liver. Once completed, this innovative project will be an invaluable resource for accessible, accurate, and responsible prediction of liver toxicity. 

Another virtual tissue model being developed is the v-embryo. This simulation investigates teratogenesis, or the production of birth defects, resulting from chemical exposures in a pregnant woman. The model is being constructed largely from zebrafish... 

Thorotrast (colloidal Th02) was once used as a radiopaque agent in medicine (see Radiopaques). Its injection in a dose of 2.0—15.0 g caused rises in body temperature, nausea, and injury to tissues at the injection site, followed by anemia, leukopenia, and impairment of the reticuloendothehal system. After intravenous adrninistration, thorotrast particles are taken up by reticuloendothehal cells of the fiver and spleen. Thorotrast is virtually not eliminated from the body (91). Between 1947 and 1961, 33 cases of cancer of the fiver, larynx, and bronchi and sarcoma of the kidneys, developing from 6 to 24 years after thorotrast administering, have been described in the literature (92). 

As a coen2yme component in tissue oxidation—reduction and respiration, riboflavin is distributed in some degree in virtually aU naturally occurring foods. Liver, heart, kidney, milk, eggs, lean meats, malted barley, and fresh leafy vegetables are particularly good sources of riboflavin (see Table 1). It does not seem to have long stabiUty in food products (8). 

Measurement of contaminants in fish has concentrated on muscle tissue since the aim has generally been to protect the health of the consumer rather than that of the fish. Endocrine tissue such as the gonads has been much more rarely examined, while data for adrenal, thyroid and pituitary levels are virtually non-existent. More data are available for the liver, as a lipid rich tissue and the major site of xenobiotic catabolism, but the concentrations have rarely been related to its capacity to produce vitellogenin or metabolise endogenous hormones. Tissue concentrations of a wide range of chemicals, are at a level which suggests that, either alone or in combination, they will cause significant endocrine disruption in fish in many polluted habitats. 

The importance of the BPG effect is evident in Figure 15.35. Hemoglobin stripped of BPG is virtually saturated with Og at a pO of only 20 torr, and it cannot release its oxygen within tissues, where the jbOg is typically 40 torr. BPG shifts the oxygen saturation curve of Hb to the right, making the Hb an Og... 

Plutonium has a much shorter half-life than uranium (24.000 years for Pu-239 6,500 years for Pu-240). Plutonium is most toxic if it is inhaled. The radioactive decay that plutonium undergoes (alpha decay) is of little external consequence, since the alpha particles are blocked by human skin and travel only a few inches. If inhaled, however, the soft tissue of the lungs will suffer an internal dose of radiation. Particles may also enter the blood stream and irradiate other parts of the body. The safest way to handle plutonium is in its plutonium dioxide (PuOj) form because PuOj is virtually insoluble inside the human body, gi eatly reducing the risk of internal contamination. 

Na+/Ca2+ exchanger activity is present in virtually evety cell type examined. The NCX1 gene is expressed in several tissues, including brain, heart, skeletal... 

Inducible NO synthase (iNOS) is usually not constitutively expressed, but can be induced in macrophages by bacterial lipopolysaccharide (LPS), cytokines and other-agents. Although primarily identified in macrophages, expression of the enzyme can be stimulated in virtually any cell or tissue, provided the appropriate inducing agents have been identified (for review see [1] and [3]). 

By manipulating the genetic machinery of the cell, it is possible to cause most cellular systems to produce virtually any biochemical material. Unfortunately, the growth of cellular systems (particularly in tissue cultures) is constrained by end-product inhibition and repression hence, it is difficult to produce end products in high concentration. Furthermore, cells are always grown in aqueous solution, so biochemicals produced by cellular routes must have intrinsically high value in order for the cost of recovery from dilute aqueous solution to be minimized. Thus, most biochemicals of commercial interest... 

A little more than half the cholesterol of the body arises by synthesis (about 700 mg/d), and the remainder is provided by the average diet. The liver and intestine account for approximately 10% each of total synthesis in humans. Virtually all tissues containing nucleated cells are capable of cholesterol synthesis, which occurs in the endoplasmic reticulum and the cytosol. 

Since the discovery of the role of NO as a vasodilator, there has been intense experimental interest in this substance. It has turned out to have a variety of physiologic roles, involving virtually every tissue of the body (Table 49—9). Three major isoforms of NO synthase have been identified, each of which has been cloned, and the chromosomal locations of their genes in hu-... 

To implement the Physiome Project, a lot of good science (Wolpert) and thinking (Dover) will be required. The tools that will ultimately define the success of the project are analytical models of biological processes that have predictive power - virtual cells, tissues, organs and systems. 

The individual modules of the in situ heart can be coupled together to compute a whole sequence from ventricular pressure development, coronary perfusion, tissue supply of metabolites, cell energy consumption, and electrophysiology, to contractile activity and ventricular pressure development in the subsequent beat. The starting point (here chosen as ventricular pressure development) can be freely selected, and drug effects on the system can be simulated. Inserted into a virtual torso, these models allow one to compute the spread of excitation, its cellular basis, and the consequences for an ECG under normal and pathological conditions. 

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